Diazo esters reaction

Aziridination remains less well developed than epoxidation. Nevertheless, high selectivity in inline aziridination has been achieved through the use of chiral sulfi-nimines as auxiliaries. Highly successful catalytic asymmetric aziridination reactions employing either sulfur ylides or diazo esters and chiral Lewis acids have been developed, although their scope and potential applications in synthesis have yet to be established. 

The BF3 Et20-catalyzed aziridination of compounds 47 (Scheme 3.15) with a diazo ester derived from (R)-pantolacetone gave aziridine-2-carboxylates 48 [59]. The reaction exhibited both high cis selectivity (>95 <5) and excellent diastereose-lectivity. Treatment of a-amino nitrile 49 (Scheme 3.16) with ethyl diazoacetate in the presence of 0.5 equivalent of SnCl4 afforded aziridines 50 and 51 in 39% yield in a ratio of 75 25 [60]. 

The reaction has also been applied to compounds with other leaving groups. Diazo ketones, diazo esters, diazo nitriles, and diazo aldehydes react with trialkylboranes in a similar manner, for example. 

Reaction of halo esters or diazo esters with boranes... 

The diazo transfer reaction between p-toluenesulfonyl azide and active methylene compounds is a useful synthetic method for the preparation of a-diazo carbonyl compounds. However, the reaction of di-tert-butyl malonate and p-toluenesulfonyl azide to form di-tert-butyl diazomalonate proceeded to the extent of only 47% after 4 weeks with the usual procedure." The present procedure, which utilizes a two-phase medium and methyltri-n-octylammonium chloride (Aliquat 336) as phase-transfer catalyst, effects this same diazo transfer in 2 hours and has the additional advantage of avoiding the use of anhydrous solvents. This procedure has been employed for the preparation of diazoacetoacetates, diazoacetates, and diazomalonates (Table I). Ethyl and ten-butyl acetoacetate are converted to the corresponding a-diazoacetoacetates with saturated sodium carbonate as the aqueous phase. When aqueous sodium hydroxide is used with the acetoace-tates, the initially formed a-diazoacetoacetates undergo deacylation to the diazoacetates. Methyl esters are not suitable substrates, since they are too easily saponified under these conditions. 

A closely related reaction employs a-diazo esters or a-diazo ketones.25 With these compounds, molecular nitrogen acts as the leaving group in the migration step. The best results are achieved using dialkylchloroboranes or monoalkyldichloroboranes. 

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

These reactions involve addition of the diazo ester to an adduct of the carbonyl compound and the Lewis acid. Elimination of nitrogen then triggers migration. Triethyloxonium tetrafluoroborate also effects ring expansion of cyclic ketones by ethyl diazoacetate.83... 

Decomposition of the diazo ester 395 in presence of dirhodium tetraacetate gives the zwitterionic intermediate 396, which undergoes a 1,3-dipolar cycloaddition with the double bond of the adjacent vinylindole. The bridged compound is isolated in good yield when the reaction is carried out at room temperature however, at 50 °C or above, compound 397 is the only compound isolated, again in good yield (Scheme 93) <2005JOC2206>. 

From ref. 64 b Reaction conditions 22 °C molar ratio 3000 (olefin)/l(catalyst)/200 (diazo ester) c 54% isolated yield reported in reference 70. Reaction conditions room temp. molar ratio 7400 (olefin)/l(catalyst)/1020(diazo ester). 

Table 6. Cyclopropanation reactions with ethyl diazoacetate using equimolar amounts of alkene and diazo ester" b... 

The common by-products obtained in the transition-metal catalyzed reactions are the formal carbene dimers, diethyl maleate and diethyl fumarate. In accordance with the assumption that they owe their formation to the competition of olefin and excess diazo ester for an intermediate metal carbene, they can be widely suppressed by keeping the actual concentration of diazo compound as low as possible. Usually, one attempts to verify this condition by slow addition of the diazo compound to an excess (usually five- to tenfold) of olefin. This means that the addition rate will be crucial for the yields of cyclopropanes and carbene dimers. For example, Rh6(CO)16-catalyzed cyclopropanation of -butyl vinyl ether with ethyl diazoacetate proceeds in 69% yield when EDA is added during 30 minutes, but it increases to 87 % for a 6 h period. For styrene, the same differences were observed 65). 

In 1966, Nozaki et al. reported that the decomposition of o-diazo-esters by a copper chiral Schiff base complex in the presence of olefins gave optically active cyclopropanes (Scheme 58).220 221 Following this seminal discovery, Aratani et al. commenced an extensive study of the chiral salicylaldimine ligand and developed highly enantioselective and industrially useful cyclopropanation.222-224 Since then, various complexes have been prepared and applied to asymmetric cyclo-propanation. In this section, however, only selected examples of cyclopropanations using diazo compounds are discussed. For a more detailed discussion of asymmetric cyclopropanation and related reactions, see reviews and books.17-21,225... 

Methyl diazoacetate was obtained according to a procedure for ethyl diazoacetate (Searle, N.E. Org. Synth., Coll. Vol. A/1963, 42). Although the experiments were usually performed with distilled methyl diazoacetate (bp 43°C at 25 mm, bath temperature below 60°C) without any problems, the cyclopropanation reaction described works equally well with undistilled diazo compound. If distilled diazo compound is desired, the submitters have stated that "a spatula of K2CO3 Is added to the crude diazo ester to trap traces of add and then distill behind a safety shield . The checkers did not evaluate this aspect of the procedure. 

A very impressive application of this chemistry is the total synthesis of (—)-ephedradine A 102.222 The key intermediate /rcarboxylic acid ester 101 was synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh2(Y-DOSP)4, aryl diazo ester 100 possessing a chiral auxiliary underwent a C-H insertion reaction to give 101 in 63% yield and 86% de (Equation (83)). 

When 2-alkyl-3-keto esters or 2-aryl-3-keto esters are treated with sulfonyl azides under basic conditions, nucleophilic deacylation occurs to yield 2-alkyl/aryl-2-diazo esters [960-963]. Nucleophilic deacylation can also be used to convert acceptor-substituted diazoketones into the corresponding acceptor-substituted diazomethanes [964,965]. In all these deacylation reactions it is the most electrophilic carbonyl group which is attacked by the nucleophile and cleaved off. 

Diazo esters can also be prepared from glycine esters by treatment with nitrous acid [966] or with alkyl nitrites. Further methods include the oxidation of hydrazones, oximes (Forster reaction), and semicarbazones, the base-induced... 

C. Crotyl diazoacetate. A solution of 10.0 g. (0.038 mole) of the />-toluenesulfonylhydrazone of glyoxylic acid chloride in 100 ml. of methylene chloride is cooled in an ice bath. Crotyl alcohol (2.80 g. or 0.038 mole) (Note 7) is added to this cold solution, and then a solution of 7.80 g. (0.077 mole) of redistilled triethyl-amine (b.p. 88.5-90.5°) in 25 ml. of methylene chloride is added to the cold reaction mixture dropwise and with stirring over a 20-minute period. During the addition a yellow color develops in the reaction mixture and some solid separates near the end of the addition period. The resulting mixture is stirred at 0° for 1 hour and then the solvent is removed at 25° under reduced pressure with a rotary evaporator. A solution of the residual dark orange liquid in approximately 200 ml. of benzene is thoroughly mixed with 100 g. of Florisil (Note 8) and then filtered. The residual Florisil, which has adsorbed the bulk of the dark colored by-products, is washed with two or three additional portions of benzene of such size that the total volume of the combined benzene filtrates is 400-500 ml. This yellow benzene solution of the diazoester is concentrated under reduced pressure at 25° with a rotary evaporator, and the residual yellow liquid is distilled under reduced pressure. (Caution This distillation should be conducted in a hood behind a safety shield) (Note 9). The diazo ester is collected as 2.20-2.94 g. (42-55%) of yellow liquid, b.p. 30-33° (0.15 mm.), n T) 1.4853 - 1.4856 (Note 10). 

Although the present procedure illustrates the formation of the diazoacetic ester without isolation of the intermediate ester of glyoxylic acid />-toluenesulfonylhydrazone, the two geometric isomers of this hydrazone can be isolated if only one molar equivalent of triethylamine is used in the reaction of the acid chloride with the alcohol. The extremely mild conditions required for the further conversion of these hydrazones to the diazo esters should be noted. Other methods for decomposing arylsulfonyl-hydrazones to form diazocarbonyl compounds have included aqueous sodium hydroxide, sodium hydride in dimethoxyethane at 60°, and aluminum oxide in methylene chloride or ethyl acetate." Although the latter method competes in mildness and convenience with the procedure described here, it was found not to be applicable to the preparation of aliphatic diazoesters such as ethyl 2-diazopropionate. Hence the conditions used in the present procedure may offer a useful complement to the last-mentioned method when the appropriate arylsulfonylhydrazone is available. 

Crotyl diazoacetate has been prepared by the procedure described here and by the reaction of diazomethane with crotyl chloroformate. The lower homolog, allyl diazoacetate, has been )repared by the reaction of allyl glycinate with nitrous acid and by the successive conversion of allyl chloroacetate to the corresponding azide, iminophosphorane, and, finally, the diazo ester. ... 

Using this approach, we have successfully predicted the major product from the cyclization of more than 30 a-diazo esters and a-diazo yS-keto esters [15]. Not all rhodium-mediated intramolecular C-H insertion reactions will proceed to give a single dominant diastereomer. Our interest in this initial investigation was to develop a model for the transition state that will allow us to discern those cyclizations that will proceed with high diastereoselectivity. 

Pirrang, Liu, and Morehead [22] have elegandy demonstrated the application of saturation kinetics (Michaehs-Menten) to the rhodium(II)-mediated insertion reactions of a-diazo /9-keto esters and a-diazo /9-diketones. Their method used the Eadie-Hofstee plot of reaction velocity (v) versus v/[S] to give and K, the equilibrium constants for the catalytic process. However, they were unable to measure the Michaelis constant (fC ) for the insertion reactions of a-diazo esters because they proved to be too rapid. 

The observed first-order rate constants, Kobs (s ) for the reaction of the rhodium] 11) complexes with diazo ester 34 varied over a range of > 10, in which the pivalate catalyst (entry 3) was almost two orders of magnitude faster than any of the other catalysts studied. The carboxamidate catalysts (entries 8-10) were slower than all the carboxy-lates, while the bridged phosphine catalyst (entry 7) behaved like most of the other car-boxy late s. 

Tab. 16.4 Observed first-order rate constants for the insertion to elimination ratios for the reaction of the rhodium(II) catalysts with diazo ester 32.

The a-diazo ester 32 with its y-branching was designed to minimize / -hydride elimination. The reaction of a-diazo methyl undecylenate 44 (Eq. 1) with Rh2(Oct)4 (42b) gave an I/A ratio of 2.8, while reaction with Rh2(MPPlM)4 (42i) gave only the /1-hydride elimination product 45. 

The 2,2 -bisindole (1384), required for the synthesis of staurosporinone (293) and the protected aglycon 1381, was prepared by a double Madelung cyclization as reported by Bergman. For the synthesis of the diazolactams 1382 and 1383, the glycine esters 1385 and 1386 were transformed to the lactams 1389 and 1390 by DCC/DMAP-promoted coupling with monoethyl malonate, followed by Dieckmann cyclization. The lactams 1389 and 1390 were heated in wet acetonitrile, and then treated with mesyl azide (MsNs) and triethylamine, to afford the diazolactams 1382 and 1383. This one-pot process involves decarboethoxylation and a diazo transfer reaction (Scheme 5.234). 

Buchanan et al. (48) reported a new route to the synthesis of the chiral hydroxy-pyrrolidines 234 and 238 from D-erythrose (230) via an intramolecular cycloaddition of an azide with an alkene (Scheme 9.48). Wittig reaction of the acetonide 230 with (carbethoxyethylene)triphenylphosphorane gave the ( ) and (Z) alkenes 231 and 232. On conversion into the triflate followed by its reaction with KN3, the ( ) isomer 231 allowed the isolation of the triazoline 234 in 68% overall yield, which on treatment with sodium ethoxide afforded the diazo ester 235 in 86% yield. 

Whereas base-induced decomposition of N-nitrosourethanes has been utilized (9) as a popular method of generating diazoalkanes, only limited investigations on base treatments of nitrosamides have been reported (10). The primary product in the base treatment is assumed, in analogy to better investigate nitrosourethane cases, to be diazo hydroxides V via attack of a base on the carbonyl group as in IV. A diazo hydroxide V has been related to the diazo ester III by a reaction with benzoyl chloride. 

In studying the reactions betw nitroso-acylamines and diazo esters several expl compds were prepd. Some reactions involved explosion hazards) 4) F. Bucci, AnnChim (Rome), 41, 587-93(1951) CA 47, 3443 (1953) (Reactions of alkali nitrites with some otg amines, such as urea may result in explns) 5) G. Armistead, ChemEngt-Progress 48, 5-10(1952) CA 46, 2298 (1952) (A review of expln hazards)... 

Carbonyl ylides possess versatile reactivities, among which the 1,3-dipolar cycloaddition is the most common and important reaction. The reaction sequence of ylide formation and then 1,3-dipolar cycloaddition can occur in either inter- or intramolecular manner. When the reaction occurs intermolecularly, the overall reaction is a one-pot three-eomponent process leading to oxygen-containing five-membered cyclic compounds, as demonstrated by the example shown in Scheme 8. A mixture of diazo ester 64, benzaldehyde, and dimethyl maleate, upon heating to reflux in CH2CI2 in the presence of 1 mol% rhodium(ii) perfluorobutyrate [Rh2(pfb)4], yields tetrahedrofuran derivative 65 in 49% yield as single diastereomer. " ... 

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